Data di Pubblicazione:
2022
Citazione:
A Small Molecule Stabilizes the Disordered Native State of the Alzheimer's Aβ Peptide / T. Löhr, K. Kohlhoff, G.T. Heller, C. Camilloni, M. Vendruscolo. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - 13:12(2022 Jun 15), pp. 1738-1745. [10.1021/acschemneuro.2c00116]
Abstract:
The stabilization of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here, we report a small molecule that stabilizes the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer's disease. We show that this stabilization takes place by a disordered binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favorable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilize disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Alzheimer’s disease; Aβ42 peptide; native state; small molecule
Elenco autori:
T. Löhr, K. Kohlhoff, G.T. Heller, C. Camilloni, M. Vendruscolo
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